TREM2 Activation by First-in-Class Direct Small Molecule Agonists: DEL Screening, Optimization, Biophysical Validation, and Functional Characterization

ABSTRACT Triggering receptor expressed on myeloid cells 2 (TREM2) is a key regulator of microglial function, and its loss-of-function variants are linked to Alzheimer’s disease (AD) and neurodegenerative disorders. While TREM2 activation is a promising therapeutic strategy, no small molecule agonists acting via direct TREM2 binding have been reported to date. Here, we describe the discovery of first-in-class, direct small molecule TREM2 agonists identified through DNA-encoded library (DEL) screening. The DEL hit ( 4a ) demonstrated TREM2 binding affinity, as validated by three biophysical screening platforms (TRIC, MST, and SPR), induced Syk phosphorylation, and enhanced microglial phagocytosis. Preliminary optimization yielded 4i , which maintained TREM2 engagement with improved selectivity over TREM1 and no cytotoxicity. Molecular dynamics simulations revealed that 4a stabilizes a transient binding pocket on TREM2, suggesting a novel mechanism for receptor activation. These findings provide the first proof-of-concept for direct pharmacological TREM2 agonism, offering a foundation for developing therapeutics against AD and related disorders. Table of Contents graphic